IL-9-dependent interstitial macrophage function in the allergic lung

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PROJECT SUMMARY / ABSTRACT: IL-9-dependent interstitial macrophage function in the allergic lung Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9 responsive cell repertoire is still not well defined. In a thorough study to identify IL-9-responsive cells, we found that IL-9 mediates pro-allergic activities by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c+/- interstitial macrophage populations. Interstitial macrophages are required for IL-9-dependent allergic responses. Mechanistically, IL-9 affects the function of lung macrophages by inducing Arg1 activity. Adoptive transfer of Arg1+ lung macrophages but not Arg1- lung macrophages can recover allergic inflammation that is lost in Il9r-/- mice. In parallel, the elevated expression of IL-9, IL-9R, and Arg1 is correlated with disease in asthma patients. Thus, our studies uncover an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation. In this renewal application we will leverage single cell RNA-seq datasets to further define the interstitial macrophage population that displays pro-allergic function. We will determine the IL-9-dependent pathways that lead to changes in macrophage gene expression. Finally, we will determine how Arg1-dependent metabolic pathways impact intrinsic gene expression in macrophages. Together, these studies will establish a detailed understanding of macrophage function in the allergic lung and identify pathways that can be explored for therapeutic value.